Method of preparing acridines and intermediates therefor

ABSTRACT

Acridines are prepared by reacting a diphenylamine-2-carboxylic acid benzenesulfonylhydrazide with a base and hydrazine, semicarbazide, thiosemicarbazide or phenylhydrazine and reacting the resulting diphenylamine-2-carboxaldehyde derivative with a mineral acid. The acridines are useful as intermediates for preparing 9-aminoalkylacridans having pharmacodynamic activity.

will llmted Statea Merit 1111 $62599 [72] Inventors Elvin L. Anderson [56] References Cited Moorestown, N..l.; UNITED STATES PATENTS 3,134,786 5/l964 Szmusckovicz 260/315 g s; gjfig 3,l58,608 11/1964 Raue 260/279 x 9 45 Patented Dec. 7, 1971 OTHER REFERENCES 73 Assignee s i 11m 3 French Laboratories Albert The Acridines," Arnold 1951, pages 57- 64 relied Philadelphia, Pa.

Primary Examiner-Donald G. Daus Anorneys-William H. Edgerton, Richard D. Foggio, Joan S. [54] W F EAQMPEgffifiwggg ffi AND Keps. Arthur R. Eglington, A1211 1). Lourie and Joseph A.

@ Claims, No Drawings Marlmo [52] US. Cl 260/279111,

260/518 A, 260/519, 260/552 R, 260/553 R, ABSTRACT: Acridines are prepared by reacting a diphen- 2 0 5 AR, 260/569 ylamine-Z-carboxylic acid benzenesulfonylhydrazide with a 511 11m. (:1 .ctm 37/16, base and hydrazine, semicarbazide-r thiosemicarbazide or C07d 37/14 phenylhydrazine and reacting the resulting diphenylamine-Z- so mend 61 Search 260/279, carboxaldehyde derivative with a mineral acid- The acridines 279 A are useful as intermediates for preparing 9-aminoalkylacridans having pharmacodynamic activity.

METHOD OF PREPARING ACRIDINES AND INTERMEDIATES THEREFOR This invention relates to a new method of preparing acridines and new intermediates in the method.

The acridines prepared by the process of this invention are represented by the following formula:

FORMULA I in which R, is hydrogen, halogen having an atomic weight of less than 80; lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethylsulfonyl, dimethylsulfamoyl or lower alkylthio.

The acridines of formula l are useful as intermediates for preparing 9-aminoalkylacridans having pharmacodynamic activity as described in U.S. Pat. No. 3,131,190. Briefly, an acridine of fonnula l is reacted with an alkylaminopropyl magnesium halide in an inert organic solvent such as an ether at about 35100 C. for about 30-180 minutes to give a 9- aminoalkylacridan which is, or is an intermediate for, a pharmacodynamically active compound as described in US. Pat. No. 3,131,190. These pharmacodynamically active 9- aminoalkylacridans have central nervous system activity and are useful as tranquilizers, ataratics, antidepressants, antiemetics, antihistaminics, antispasmodics and anti-inflammatory agents.

An advantageous compound of formula 1 is that in which R is chloro, in particular, in the 2-position, that compound being 2-chloroacridine. This acridine is an intermediate in the preparation of 9-aminoalkyl- 2-chloroacridans, in particular, 2-chloro- Q-dimethylaminopropylacridan which is a known tranquilizing agent, Simpson, et al., Current Therapeutic Research 8:447-451 (1966 and Claghorn, et al., Psychosomatics 8:212-215 (1967).

The process of this invention is represented schematically as follows:

in which:

R; is hydrogen, halogen having an atomic Weight of less than 80, lower alkyl, lower alkoxy, trifluoromethyl, trifiuoromethylsulfonyl, dimethylsulfamoyl or lower alkylthio; R is I g I NH NHrorNH- and Ar is phenyl, tolyl preferably p-tolyl or dihalophenyl preferably 2,5-dichlorophenyl.

The intermediates of formula 111 above are also objects of this invention.

A preferred process of this invention and preferred intermediates of Formula. III are represented above when R is and R, is chloro in the position para to the attachment of the nitrogen atom.

According to the above process, a diphenylamirie-Z-carbbxylic acid benzenesulfonylhydrazide of formula 11 is reacted with a base such as an alkali metal hydroxide, for example, sodium or potassium hydroxide, or an. alkali metal carbonate, for example, sodium or potassium carbonate, and a member selected from the group consisting of hydrazine, semicarbazide, thiosemicarbazide and phenylhydrazine to give a diphenylamine- 2-carboxaldehyde derivative of formula III. This reaction is carried out in an organic solvent preferably a hydroxylic solvent such as, for example, fl-ethoxyethanol, B- methoxyethanol, ethylene glycol, butanol or amyl alcohol, advantageously in an aqueous solution with a water miscible hydroxylic solvent such as B-ethoxyethanol or B-methoxyethanol. The reaction is carried out at elevated temperature preferably about 200 C., conveniently at reflux temperature.

The above prepared diphenylamzine- Z-carboxaldehyde derivatives are reacted with a mineral acid such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid to give the acridines. The reaction is carried out in an organic solvent, for example, a lower alkanoic acid such as acetic or formic acid or a hydroxylic solvent such as B-ethoxyethanol, methoxyethanol or ethylene glycol, preferably a lower alkanoic acid. Preferably, the reaction is carried out at elevated temperature, such as, for example, about l00-200 C.

The diphenylamine-Z-carboxylic acid benzenesulfonylhydrazide compounds are prepared as follows:

1. by reacting a diphenylamine- 2-carboxylic acid with a chlorinating agent, for example, thionyl chloride, to give the corresponding carboxylic acid chloride and reacting the acid chloride with a benzenesulfonylhydrazine or 2. by reacting a lower alkyl ester of a diphenylamine-Z-carboxylic acid with hydrazine and benzenesulfonyl chloride.

The diphenylamine-2-carboxylic acids are either known to the art or are prepared by known methods, for example, by reacting a R substituted aniline with an o-halobenzoic acid or by reacting an o-aminobenzoic acid with an R,-substituted halobenzene.

The following examples are not limiting but are illustrative of the process and intermediates of this invention.

EXAMPLE 1 A mixture of 247.5 g. of 4'-chlorodilphenylamine-Z-carboxylic acid, g. of thionyl chloride and 2 liters of cyclohexane is heated at reflux for 1 hour with mechanical stirring. The resulting solution is cooled to 40-50 C. and 223 g. of ptoluenesulfonylhydrazine is added. The mixture is then heated under reflux for 6 hours with stirring, then cooled and filtered. The solid material is dried in vacuo to give 4'-chlorodiphenylamine-Z-carboxylic acid p-toluenesulfonylhydrazide.

A mixture of 104 g. of W-chlorodiphenylamine- 2-carboxylic acid p-toluenesulfonylhydrazide, 50 ml. of 10N sodium hydroxide, 400 ml. of B-ethoxyethanol, 250 ml. of water and 15 g. of 85 percent hydrazine hydrate is heated at reflux for 2 hours with mechanical stirring. The mixture is cooled and filtered. The solid material is dried in vacuo to give 4'- chlorodlphenylamlne- Z-carboxaldehyde azine.

A mixture of 131 g. of 4'-chlorodiphenylamine-2-carboxaldehyde azine, 400 ml. of glacial acetic acid and 122 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for 1 hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered. Drying the solid material in vacuo gives 2- chloroacridine.

EXAMPLE 2 A mixture of 50 g. of 4'-trifluoromethyldiphenylamine-2- carboxylic acid, 24 g. of thionyl chloride and 500 ml. of cyclohexane is heated at reflux with mechanical stirring for 1 hour. The solution is cooled to 40-50 C. and 37.2 g. of ptoluenesulfonylhydrazine is added. The resulting mixture is heated for 6 hours at reflux, cooled and the insoluble solid is removed by filtration and dried in vacuo to give 4- trifluoromethyldiphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide.

A mixture of 272 g. of 4'-trifluoromethyldiphenylamine-2- carboxylic acid p-toluenesulfonylhydrazide, 120 ml. of N sodium hydroxide, 1.1 liter of B-ethoxyethanol, 680 ml. of water and 36.5 g. of 85 percent hydrazine hydrate is heated at reflux with mechanical stirring for 2 hours. The mixture is cooled and the solid removed by filtration and dried in vacuo to give 4'-trifluoromethyldiphenylamine- 2-carboxaldehyde azme.

A mixture of 90 g. of 4'-trifluoromethyldiphenylamine-2- carboxaldehyde azine. 270 ml. of glacial acetic acid and 73 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for 1 hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The solid material is removed by filtration and dried in vacuo to give 2-trifluoromethylacridine.

EXAMPLE 3 A mixture of 156.5 g. ofo-chlorobenzoic acid, 167.2 g. of p- (n-butyl)aniline, 69 g. of potassium carbonate, 1 g. of copperbronze powder and 350 ml. of isoamyl alcohol is heated at reflux with mechanical stirring for 4 hours. During this time the water which formed is removed by azeotropic distillation. The inorganic salts are removed by filtration and 30 ml. of glacial acetic acid is added to the filtrate. After cooling, the solid material is removed by filtration and dried in vacuo to give 4'- (n-butyl)diphenylamine-2-carboxylic acid.

A mixture of 26.9 g. of 4'-(n-butyl)diphenylamine-Z-carboxylic acid, 13.2 g. of thionyl chloride and 270 ml. of benzene is heated at reflux with mechanical stirring for 1 hour. The solution is cooled to 4045 C. and 20.5 g. of ptoluenesulfonylhydrazine is added. The resulting mixture is heated at reflux for 6 hours, cooled to 5-10 C. and the insoluble solid removed by filtration and dried in vacuo to give 4'-(n-butyl)diphenylamine- Z-carboxylic acid p-toluenesulfonylhydrazide.

A mixture of 25 g. of 4'-(n-butyl)diphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide, 11.5 ml. of ION sodium hydroxide, 100 ml. of Bethoxyethanol, 60 ml. of water and 3.5 g. of 85 percent hydrazine hydrate is heated at reflux with mechanical stirring for 2 hours. The mixture is cooled and the solid removed by filtration and dried in vacuo to give 4' -(nbutyl)diphenylamine-Z-carbox aldehyde azine.

A mixture of 7 g. of 4'-( n-butyl)diphenylamine-2carboxaldehyde azine, 25 ml. of glacial acetic 1010 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for 1 hour. The solution is diluted with ice and hydrate and basified with sodium hydroxide solution. The solid material is removed by filtration, dissolved in ether and the residue is crystallized from hexane to give 2-(n-butyl)-acridine.

EXAMPLE 4 A mixture of 85 g. of 2'-chlorodiphenylamine-2-carboxylic acid, 47.4 g. of thionyl chloride and 850 ml. of benzene is heated at reflux with mechanical stirring for 1 hour. The solution is cooled to 40-50 C., 76.5 g. of p-toluenesulfonylhydrazine is added and the resulting mixture is heated at reflux with stirring for 6 hours. The mixture is cooled to 5-10 C. and the solid material is removed by filtration and dried in vacuo to give 2-chlorodiphenylamine-2'carboxylic acid ptoluenesulfonylhydrazide.

A mixture of 138 g. of 2-chlorodiphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide, 66.2 ml. of lON sodium hydroxide, 550 ml. of B-ethanoxyethanol, 250 ml. of water and 19.5 g'. of percent hydrazine hydrate is heated at reflux with mechanical stirring for 2 hours. The mixture is cooled and the solid material is removed by filtration and dried in vacuo to give 2-chlorodiphenylamine-2-carboxaldehyde azme.

A mixture of 51.5 g. of 2'-chlorodiphenylamine-Z-carboxaldehyde azine, 155 ml. of glacial acetic acid and 48 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for 1 hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The precipitate is removed by filtration and dried in vacuo to give 4-chloroacridine.

EXAMPLE 5 A mixture of 155 g. of 2'-trifluoromethyldiphenylamine-2- earboxylic acid, 76.5 g. of thionyl chloride and 1,600 ml. of benzene is heated at reflux with mechanical stirring for 1 hour. The solution is cooled to 4050 C., 123 g. of p-toluenesulfonylhydrazine is added and'the resulting mixture is heated under reflux with stirring for 6 hours. The suspension is cooled and the insoluble solid is removed by filtration and dried in vacuo to give 2f-trifluoromethyldiphenylamine-Z-carboxylic acid p-toluenesulfonylhydrazide.

A mixture of 166 g. of 2i-trifluoromethyldiphenylamine-Z- carboxylic acid p-toiuenesulfonylhydrazide, 74 ml. of 10N sodium hydroxide, 665 ml. of B-ethoxyethanol, 415 ml. of water and 22 g. of 85 percent hydrazine hydrate is heated at reflux with mechanical stirring for 2 hours. The mixture is cooled and the insoluble solid is removed by filtration and dried in vacuo to give 2'-trifluoromethyldiphenylamine-2-carboxaldehyde azine.

A mixture of 37.5 g. of 2'-trifluoromethyldiphenylamine-2- carboxaldehyde azine, 113 ml. of glacial acetic acid and 30 ml. of concentrated hydrochloric acid is heated at reflux with mechanical stirring for l hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The insoluble solid is removed by filtration and dried in vacuo to give 4-trifluoromethylacridine.

EXAMPLE 6 A mixture of 416 g. of 4'-ch1orodiphenylamine-Z-carboxylic acid p-toluenesulfonylhydrazide (prepared as in example 1), g. of sodium hydroxide, 1,600 mi. of B-ethoxyethanol, 1,200 ml. of water and 1 14.5 g. of semicarbazide hydrochloride is heated at reflux with mechanical stirring for 1.5 hours. To the hot solution is added an additional 600 ml. of water and the mixture is cooled. The solid material is removed by filtration and dried in vacuo to give 4'- chlorodiphenylamine-2-carboxaldehyde semicarbazone.

A mixture of 72 g. of 4'-chlorodiphenylamine-Z-carboxaldehyde semicarbazone, 200 ml. of glacial acetic acid and 61 ml. of concentrated hydrochloric acid is heated at reflux with stirring for 1 hour. The reaction mixture is worked up as in example 1 to give 2-chloroacridine.

EXAMPLE 7 A mixture of 29.2 g. of 3 '-bromodiphenylamine-2-carboxy1- ic acid, 13.5 g. of thionyl chloride and 200 m1. of cyclohexane is heated at reflux for 1 hour with stirring. The solution is then cooled to 40S0 C. and 20.6 g. of benzenesulfonylhydrazine is added. The resulting mixture is heated at reflux for 6 hours with stirring, cooled and filtered to give 3'-brom0diphenylamine-Z-carboxylic acid benzenesulfonylhyrazide.

A mixture of 44 g. of 3-bromodiphenylamine-2-carboxylic acid benzenesulfonylhydrazide, 12 g. of sodiumhydroxide 160 ml. of ,B-ethoxyethanol, 120 ml. of water and 12.8 g. of thiosemicarbazide hydrochloride is heated at reflux with stir ring for 2 hours. An additional 60 ml. of water is added to the hot solution. The mixture is cooled and filtered to give 3- bromodiphenylamine-Z-carboxaldehyde thiosemicarbazone.

The above prepared thiosemicarbazone is refluxed with glacial acetic acid and concentrated hydrochloric acid by the procedure of example 6 to give 3-bromoacridine and lbromacridine.

EXAMPLE 8 A mixture of 140 g. of 4-chlorodiphenylamine-Z-carboxylic acid p-toluenesulfonylhydrazide (prepared as in example 1), 27 g. of sodium hydroxide, 36.4 g. of phenylhydrazine, 500 ml. of B-ethoxyethanol and 200 ml. of water is heated at reflux with mechanical stirring for 2 hours. The mixture is cooled and the solid material is removed by filtration and dried in vacuo to give 4'-chlorodiphenylamine-Z-carboxaldehyde phenylhydrazone.

A mixture of 80 g. of 4-chlorodiphenylamine-2-carboxaldehyde phenylhydrazone, 200 ml. of glacial acetic acid and 33 ml. of concentrated sulfuric acid is heated at reflux with stirring for 1 hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered to give 2- chloroacridine.

EXAMPLE 9 fonylhydrazide.

A mixture of 75 g. of 4'-methylthiodiphenylamine-2-carboxylic acid p-toluenesulfonylhydrazide, 35 ml. of ION sodium hydroxide solution, 320 ml. ofB-ethoxyethanol, 200 ml. of water and I0 g. of 85 percent hydrazine hydrate is heated at reflux with stirring for 2 hours. The mixture is cooled and the solid material is removed by filtration and dried in vacuo to give 4'-methylthiodiphenylamine-Z-carboxaldehyde azine.

A mixture of 7 g. of 4-methylthiodiphenylamine-Z-carboxaldehyde azine, 25 ml. of glacial acetic acid and 7.5 ml. of concentrated hydrochloric acid is heated at reflux with stirring for 1 hour. The solution is diluted with ice and water and basified with sodium hydroxide solution. The insoluble solid is removed by filtration and dried in vacuo to give 2- methylthioacridine.

EXAMPLE ID A mixture of 35 g. of 4'-methyldiphenylamine-2-carboxylic acid, 24 g. of thionyl chloride and 500 ml. of cyclohexane is heated at reflux with stirring for 2 hours. The solution is cooled and 48 g. of 2,5dichlorobenzenesulfonylhydrazine is added. The resulting mixture is heated at reflux for 6 hours, then cooled and filtered to give 4'-methyldiphenylamine-2- carboxylic acid 2,5-dichlorobenzenesulfonylhydrazide.

A mixture of 27 g. of the above prepared 2,5- dichlorobenzenesulfonylhydrazide, 6.4 g. of sodium carbonate, l ml. of B-ethoxyethanol, 68 ml. of water and 3.7 g. of 85 percent hydrazine hydrate is heated at 100 C. with stirring for 3 hours. The mixture is cooled and filtered to give 4'- methyldiphenylamine-Z-carboxaldehyde azine.

A mixture of 7 g. of the above prepared azine, ml. of formic acid and 1001]. ofphosphoric acid is heated at reflux for 2 hours. The solution is diluted with ice and water, basified with sodium hydroxide and filtered to give 2-methylacridine.

EXAMPLE 1 l A mixture of 43 g. of 2'-methoxydiphenylamine'2-carboxylic acid, 24 g. of thionyl chloride and 500 ml. of cyclohexane is heated at reflux with stirring for 1 hour. The solution is cooled to 45 C. and 34.4 g. of benzenesulfonylhydrazine is added. The mixture is heated for 6 hours at reflux, then cooled and filtered to give 2-methoxydiphenylamine-2-carboxylic acid benzenesulfonylhydrazide.

A mixture of 13 g. of the above prepared benzenesulfonylhydrazide, 3.8 g. of potassium hydroxide, 3.6 g. of phenylhydrazine and 50 ml. of ethylene glycol is heated at 200 C. with stirring for 2 hours. The mixture is cooled and filtered to give 2'-methoxydiphenylamine-2-carboxaldehyde phenylhydrazone.

A mixture of 7.9 g. of 2'-methoxydi phenylamine-Z-carboxaldehyde phenylhydrazone, 10 ml. of concentrated sulfuric acid and 50 ml. of ethylene glycol is heated at 150 C. for 1 hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered to give 4-methoxyacridine.

EXAMPLE 12 A mixture of 34.5 g. of 4'-trifluoromethylsulfonyldiphenylamine-2-carboxylic acid, 13.5 g. of thionyl chloride and 200 ml. of cyclohexane is heated at reflux with stirring for l hour. The solution is cooled to 4050 C. and 22.3 g. of ptoluenesulfonylhydrazine is added. The mixture is heated at reflux with stirring for 6 hours, then cooled and filtered to give 4i'-trifluoromethylsulfonyldiphenylamine-2carboxylic acid ptoluenesulfonylhydrazide.

A mixture of 12.8 g. of the above prepared p-toluenesul fonylhydrazide, 3.5 of potassium carbonate, 45 ml. of Bmethoxyethanol, 25 ml. of water and 1.5 g. of percent hydrazine hydrate is heated at reflux for 2 hours with stirring. The mixture is cooled and filtered to give 4-trifluoromethylsulfonyldiphenylamine-2-carboxaldehyde azine.

A mixture of 8.8 g. of the above prepared azine, 7.5 ml. of concentrated hydrochloric acid and 20 ml. ofB-ethoxyethanol is heated at reflux for 1 hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered to give 2-trifluoromethylsulfonylacridine.

EXAMPLE 13 A mixture of 47 g. of 4'-(N,N-dimethylsulfamoyl)diphenylamine-2-carboxylic acid benzenesulfonylhydrazide (prepared from 4'-(N,N-dimethylsulfamoyl )diphenylamine-2- carboxylic acid by the procedure of example 7), 12.0 g. of sodium hydroxide, 160 ml. of ,B-ethoxyethanol, ml. of water and 11.4 of semicarbazide hydrochloride is heated at reflux with stirring for 2 hours. Water (60 ml.) is added to the hot solutionand the mixture is cooled and filtered to give 4'- (N,N-dimethylsulfamoyl )diphenylamine-2-carboxaldehyde semicarbazone.

A mixture of 36 g. of the above prepared semicarbazone, ml. of glacial acetic acid and 48 ml. of concentrated hydrochloric acid is heated at reflux with stirring for l hour. The solution is diluted with ice and water, basified with sodium hydroxide solution and filtered to give 2-(N,N-dimethylsulfamoyl)acridine.

EXAMPLE l4 A mixture of 9.5 g. of diphenylamine-Z-carboxylic acid ptoluenesulfonylhydrazide, 5 ml. of lON sodium hydroxide, 1.5 g. of 85 percent hydrazine hydrate, 50 ml. of ,B-methoxyethanol and 20 ml. of water is heated at reflux with stirring for 2 hours. The mixture is cooled and filtered to give diphenylamine-2-carboxaldehyde azine.

A mixture of 5.7 g. of diphenylamine-Z-carboxaldehyde azine, 7.5 ml. of concentrated hydrochloric acid and 100 ml. of B-methoxyethanol is heated at 100 C. for 2 hours. The

solution is diluted with water and ice, basified with aqeuous sodium hydroxide solution and filtered to give acridine.

What is claimed is:

1. A method of preparing acridines of the formula:

in which R, is hydrogen, halogen having an atomic weight of less than 80, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethylsulfonyl, dimethylsulfamoyl or lower alkylthio which comprises reacting a diphenylamine-Z-carboxylic acid benzenesulfonylhydrazide of th eforrnula z i WQQNENH s in which:

R is as previously defined; and

Ar is phenyl, p-tolyl or 2,5-dichlorophenyl, with a base selected from the group consisting of an alkali metal hydroxide and an alkali metal carbonate, and a member selected from the group consisting of hydrazine, semicarbazide, thiosemicarbazide and phenylhydrazine in a hydroxylic solvent at elevated temperature to give an in- S ILHikNH: or ill-Q isolating the intermediate compound and reacting the intermediate compound with a mineral acid selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid in a solvent selected from the group consisting of a lower alkanoic acid and a hydroxylic solvent.

2. A method according to claim 1 in which the diphenylamine-Z-carboxaldehyde derivative is reacted with hydrochloric acid in glacial acetic acid at elevated temperature.

3. A method according to claim 1 in which R is 4. A method according to claim 1 in which R is and R, is I chloro in the position para to the attachment of the nitrogen atom.

5. A method of preparingacridines of the formula:

in which R is hydrogen, halogen having an atomic weight of le 5 than 80, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethylsulfonyl, dimethylsulfamoyl or lower alkylthio which comprises reacting a compound of the formula:

in which:

R is as previously defined;

with a mineral acid selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid in a solvent selected from the group consisting of a lower alkanoic acid and a hydroxylic solvent.

6. A method according to claim 5 in which the diphenylamine-Z-carboxaldehyde derivative is reacted with hydrochloric acid in glacial acetic acid at elevated temperature.

7. A method according to claim 5 in which R is 8. A method according to claim 5 in which R is and R is chloro in the position para to the attachment of the nitrogen atom.

l l i I! l llllllll 2 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,625,945 Dated' December 7, 1971 lnvent fl Elvin L. Anderson and Harold Grabqyes It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 7, line 47, the formula reading .1

III I?! NHCNH should read NHCNH Column 8, line 45, the formula reading .I ll In NI-ICNI-I should read NHCNH Signed and sealed this 11 th day of July 1 972..

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOITSCHALK Attesting Officer I Commissioner of Patents 

2. A method according to claim 1 in which the diphenylamine-2-carboxaldehyde derivative is reacted with hydrochloric acid in glacial acetic acid at elevated temperature.
 3. A method according to claim 1 in which R2 is
 4. A method according to claim 1 in which R2 is
 5. A method of preparing acridines of the formula:
 6. A method according to claim 5 in which the diphenylamine-2-carboxaldehyde derivative is reacted with hydrochloric acid in glacial acetic acid at elevated temperature.
 7. A method according to claim 5 in which R2 is
 8. A method according to claim 5 in which R2 is 